The ability to form associative memories is one of the most important functions of an organism's nervous system. However, the molecular mechanisms underlying learning and associative memory formation have yet to be fully elucidated. Identifying molecules involved in these processes is important not only to gain an understanding of normal brain function, but can also lead to an understanding of disease states such as age-related cognitive decline and Alzheimer's disease. We will use the nematode Caenorhabditis elegans, which has a simple nervous system and its genes have conserved functions in higher organisms, to identify molecules that are most essential for learning and memory. We will identify these molecules combining two techniques developed in our lab, a novel long-term associative memory (LTAM) assay and RNA-seq of individual populations and compartments of neurons.
In Aim 1, we will identify postsynaptic molecules that are involved in regulation of LTAM by labeling postsynapses with a translational RFP fusion of a scaffolding protein important for learning and memory, MAGI-1. After LTAM training, MAGI-1:RFP worms will be lysed and subjected to FACS in order to isolate fluorescent postsynaptic compartments. RNA will be purified from the neurons and subjected to RNA-seq. We will then determine the profile of postsynaptic genes induced by memory training.
In Aim 2 we will characterize mRNAs identified in Aim 1.
In Aim 2 a we will use utilize RNAi and deletion strains to identify novel and conserved postsynaptic regulators of learning and memory.
In Aim 2 b, we will determine which mRNAs of interest may be locally translated by utilizing single molecule fluorescent in situ hybridization. Bioinformatic analysis of these RNAs will also reveal potential RNA binding proteins that regulate LTAM.
In Aim 2 c, we will determine if the protein products of mRNAs identified in Aims 2a and 2b are also synaptically localized. This will allow us to identify novel proteins that are located in the postsynaptic density and may regulate synaptic remodeling during learning and memory.
In Aim 3, we will determine if aging causes defects in the postsynaptic processes involved in LTAM, including transcriptional reprogramming, local translation, and postsynaptic remodeling. We will accomplish this by repeating the experiments in Aim 1 and 2 in aged worms, to identify molecules that contribute to age-related cognitive decline.

Public Health Relevance

The ability to form associative memories is one of the most important functions of an organism's nervous system, and the loss of this ability is the hallmark of several disorders such as age-related cognitive decline, dementia, and Alzheimer's disease; however, the factors that regulate long-term memory formation have yet to be fully elucidated. The proposed research will identify novel and conserved molecules that are critical for learning and memory formation and the decline of these processes with age, and may lead to therapies to improve or maintain cognitive abilities with age.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Wagster, Molly V
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Princeton University
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Arey, Rachel N; Murphy, Coleen T (2017) Conserved regulators of cognitive aging: From worms to humans. Behav Brain Res 322:299-310
Li, Ling-Bo; Lei, Haoyun; Arey, Rachel N et al. (2016) The Neuronal Kinesin UNC-104/KIF1A Is a Key Regulator of Synaptic Aging and Insulin Signaling-Regulated Memory. Curr Biol 26:605-15
Kaletsky, Rachel; Lakhina, Vanisha; Arey, Rachel et al. (2016) The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult phenotype regulators. Nature 529:92-6
Lakhina, Vanisha; Arey, Rachel N; Kaletsky, Rachel et al. (2015) Genome-wide functional analysis of CREB/long-term memory-dependent transcription reveals distinct basal and memory gene expression programs. Neuron 85:330-45